Open angle glaucoma (OAG) is a prevalent disease that results in irreversible loss of vision through the death of retinal ganglion cells (RGCs). Although several risk factors for OAG have been identified, including elevated intraocular pressure (IOP), the exact molecular mechanisms leading to OAG remain poorly understood. It remains to be determined how systemic blood pressure (BP) and gender contribute to OAG. Finally, available therapies delay disease progression but offer incomplete protection, and development of new therapeutic strategies has been hampered by the lack of animal models of OAG. Our preliminary data establish mice deficient in the nitric oxide (NO) receptor soluble guanylate cyclase ?1 (sGC??1 -/-) as a new animal model for OAG, and identify sGC??1 -/- mice as a unique model to study the relation between blood pressure, gender, and OAG. Furthermore, this new animal model of moderately increased IOP and OAG represents an important tool to teststrategies for disease prevention and treatment of elevated IOP and OAG. We hypothesize that sGC??1 -deficiency predisposes RGCs to modest IOP increases in a gender-specific manner. Our hypothesis will be tested in three specific aims. Aim 1 - Determine the role of gender and BP in the development of OAG in sGC??1 -/- mice. Objective A - Determine whether male sGC??1 -/- mice develop OAG. Objective B - Test whether sex-hormones affect the development of OAG in sGC??1 -/- mice. Objective C - Investigate whether BP modulates OAG risk in sGC??1 -/- mice. Aim 2 - Test whether sGC??1 -deficiency predisposes to optic neuropathy associated with elevated IOP. Objective A - Study the effect of increasing IOP (with microbeads) on the retinal nerve fiber layer (RNFL) and the optic nerve (ON) in young WT and sGC??1 -/- mice. Objective B - Assess retinal and ON damage in mice in which sGC??1 is selectively deficient in RGCs. Aim 3 - Investigate the ability of available compounds that enhance cGMP signaling to prevent optic neuropathy in OAG associated with sGC??1 -deficiency. Objective - Serially measure the impact of treating sGC??1 -/- mice with the cGMP-elevating compounds sildenafil (a phosphodiesterase (PDE) 5-antagonist), brain natriuretic peptide (BNP, a peptide activator of membrane bound guanylate cyclase (pGC)), and cinaciguat (an sGC-activator) on AqH outflow, IOP, RNFL thickness, and ON axon count. We anticipate that the studies described in this proposal will further our knowledge of the etiology o OAG by elucidating the role of impaired NO-cGMP signaling, gender, and BP in the development of OAG. We furthermore expect to identify cGMP signaling as a promising therapeutic target in the treatment of OAG. PUBLIC HEALTH RELEVANCE: Our preliminary data identify mice deficient in the ?1 subunit of soluble guanylate cyclase (sGC??1 -/- mice) as a novel and unique model of open angle glaucoma (OAG). This research project aims to i) elucidate the role of impaired NO-cGMP signaling, gender, and ocular perfusion pressure in the development of OAG, ii) further our knowledge of the etiology of OAG, focusing on the susceptibility of retinal ganglion cells to changes in IOP, and iii) identify cGMP signaling as a therapeutic target in the treatment of OAG.